JP6903273B1 - Compounds or salts thereof, and radioactive sensitizers - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel pharmaceutical compound which can be used in combination with radiation in tumor treatment. SOLUTION: A compound represented by the following formula (I) or a salt thereof. In the formula (I), R1 is an aliphatic hydrocarbon group of C1 to C26. [Selection diagram] FIG. 19

Description

The present invention relates to a compound or a salt thereof, and a radioactive sensitizer.

Half of the causes of death in Japanese are malignant tumors, heart disease, and cerebrovascular disease (2017 Ministry of Health, Labor and Welfare vital statistics). Malignant tumors are the leading cause of death and are still on the rise. Surgical therapy, chemotherapy and radiation therapy are known as the three major therapeutic methods for malignant tumors. In order to emphasize the quality of life (QOL) of patients, radiation therapy such as external irradiation using electron beam, X-ray, gamma ray, proton beam, or heavy particle beam, or internal irradiation such as brachytherapy is performed. Attention has been paid.

Pyrimidine halides and hypoxic cell sensitizers are known as chemical or pharmaceutical substances that are administered at the same time as radiation in radiotherapy and that enhance the therapeutic effect, that is, those that can be clinically put into practical use as radiosensitizers. (See, for example, Non-Patent Document 1). Further, as a hypoxic cell sensitizer, misonidazole and the like are known.

Patent Document 1 discloses, as another radiosensitizer, a radiosensitizer composed of sulfopyranosylacylglycerol or a salt thereof. Further, Patent Document 2 discloses a radioactive sensitizer composed of a sulfoquinobosyl acylpropanediol or a salt thereof.

Japanese Patent No. 3927991 Japanese Patent No. 4435861

Eric J. Hall et al., Translated by Soho Urano, "Radiobiology for Radiologists", Shinohara Publishing Shinsha, November 1, 1995 Junko Takahashi, 2 others, "Verification of X-ray sensitized radiotherapy of aminolevulinic acid and elucidation of mechanism of action by gene expression analysis", [online], 2017, Grant-in-Aid for Scientific Research, [Reiwa 2] Searched on September 10, 2014], Internet <URL: https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-25293270/> Lei Li et al., “Functional biomimetic nanoparticles for drug delivery and theranostic applications in cancer treatment”, Science and Technology of Advanced Materials, 2018 Oct 26; vol.19 (1): p.771-790

However, the radiosensitizer as described in Non-Patent Document 1 has problems to be solved such as gastrointestinal disorders, peripheral neurotoxicity, and other side effects, and has hardly been put into practical use. Therefore, there is a demand for new pharmaceutical compounds that can be utilized for treatment using radiation.

An object of the present invention is to provide a novel pharmaceutical compound that can be used in combination with radiation in tumor treatment.

前記式（Ｉ）中、Ｒ_１はＣ _１０ 〜Ｃ _２６ の脂肪族炭化水素基である。 In order to achieve the object of the present invention, for example, the compound according to one embodiment has the following constitution. That is, it is a compound represented by the following formula (I) or a salt thereof.

In the formula (I), R ₁ is an aliphatic hydrocarbon group of C _{10 to} C _26.

To provide a novel pharmaceutical compound that can be used in combination with radiation in tumor treatment.

The figure which shows the mass spectrometry result of the compound of structural formula (3). The figure which shows the result ^{of 1 1} H-NMR measurement of the compound of structural formula (3). The figure which shows the mass spectrometry result of the compound of structural formula (4). The figure which shows the result ^{of 1 1} H-NMR measurement of the compound of structural formula (4). The figure which shows the mass spectrometry result of the compound of structural formula (5). The figure which shows the result ^{of 1 1} H-NMR measurement of the compound of structural formula (5). The figure which shows the result ^{of 1 1} H-NMR measurement of the compound of structural formula (6). The figure which shows the mass spectrometry result of the compound of structural formula (6). The figure which shows the result ^{of 1 1} H-NMR measurement of the compound of structural formula (7). The figure which shows the mass spectrometry result of the compound of structural formula (7). The figure which shows the result ^{of 1 1} H-NMR measurement of the compound of structural formula (8). The figure which shows the mass spectrometry result of the compound of structural formula (8). The figure which shows the result ^{of 1 1} H-NMR measurement of the compound of structural formula (9). The figure which shows the mass spectrometry result of the compound of structural formula (9). The figure which shows the result ^{of 1 1} H-NMR measurement of the compound of structural formula (10). The figure which shows the mass spectrometry result of the compound of structural formula (10). The figure which shows the result ^{of 1 1} H-NMR measurement of the compound of structural formula (11). The figure which shows the mass spectrometry result of the compound of structural formula (11). The figure which shows the experimental result of radiosensitivity. The figure which shows the experimental result of hydrolysis resistance.

Hereinafter, embodiments will be described in detail with reference to the accompanying drawings. The following embodiments do not limit the invention according to the claims, and not all combinations of features described in the embodiments are essential to the invention. Two or more of the plurality of features described in the embodiments may be arbitrarily combined. In addition, the same or similar configuration will be given the same reference number, and duplicate description will be omitted.

The compound according to one embodiment of the present invention is represented by the following general formula (I).

In the general formula (I), R ₁ is an aliphatic hydrocarbon group. The _{number of carbon atoms contained in R 1} is not particularly limited, but may be, for example, 1 or more, 3 or more, 10 or more, 12 or more, 14 or more. It may be more than or equal to 16 or more. Further, the _{number of carbon atoms contained in R 1} may be 26 or less, 24 or less, and more preferably 22 or less. Examples of aliphatic hydrocarbon groups include alkyl groups such as methyl, hexyl, dodecyl, octadecyl or icosyl groups, alkenyl groups such as hexenyl, dodecenyl, octadecenyl, or icosenyl groups, and dodecynyl. Examples include alkynyl groups such as groups, octadecynyl groups, or icosinyl groups.

In one embodiment, the quinovose ring contained in the compound of general formula (I) (3- (n-octadecyloxy) -n-propylsulfokinovoside derivative) may be boat-shaped or chair-shaped. Although they may be mixed, the chair type is generally preferable because it is more stable. Although propanediol quinovose ring in the general formula (I) (-O-C 3 H 6 -OR 1) is attached, the configuration of the quinovose ring in the propanediol even α anomer Often, they may be β-anomers, or they may be mixed.

In the synthetic process in one embodiment, the R1 moiety in general formula (I) is provided with an alcohol compound. This alcohol compound may be a saturated alcohol or an unsaturated alcohol. Further, the alcohol compound may be linear or branched. Examples of saturated alcohols include 1-hexanol, 1-octadecanol and the like. Examples of unsaturated alcohols include 1-hexene-6-ol and 1-octadecene-18-ol.

The compound according to a further embodiment of the present invention is a salt of the compound represented by the above general formula (I). As the salt, for example, a monovalent cation salt such as sodium and potassium, or a divalent cation salt such as calcium and magnesium may be used. In the present invention, for example, the sulfo group in the formula (I) may be a salt.

The method for synthesizing the compound represented by the general formula (I) is not particularly limited, but the compound is synthesized according to the following routes A to J. By treating the obtained compound (11) with an acid, a compound represented by the general formula (I) can be obtained. Since no new asymmetric carbon is generated in the following synthesis process, production is easy. Further, according to the following synthesis process, it is easy to produce a compound with high purity.

Further, in the synthesis method described in Patent Document 1, the terminal 20 bond of the allyl group is hydroxyated to construct a glycerol skeleton, and the 2-position of the glycerol site becomes an asymmetric carbon. Is produced at a ratio of approximately 1: 1. Such compounds are not suitable for use as pharmaceuticals, and when it is attempted to selectively synthesize each of the three isomers, the process becomes complicated and the cost is disadvantageous.

In addition, the sulfopyranosylacylglycerol derivative also has a number of structural isomers (2-acyls) in which the acyl group at the 1-position of glycerol (1-acyl form) is transferred to the 2-position between and / or between the molecules. % Generate. Since these stereoisomers or structural isomers are produced even during storage, it is chemically difficult to supply a highly pure sulfopyranoside acylglycerol derivative. On the other hand, on the other hand, stored in a state compound represented by the general formula (I) according to one embodiment, since the prone hydroxy groups metastasis in the vicinity of the R ₁ group is not present, the structurally stable can do.

Here, "Cm: n" indicates that _{the number of carbon atoms contained in one} R group of the general formula (I) is m and the number of double bonds is n (m is n). 1 or more, n is an integer of 0 or more). Further, "Ph" indicates a phenyl group, "Bn" indicates a benzyl group, "Ts" indicates a tosyl group, and "SAc" indicates a thioacetyl group.

The salt of the compound according to one embodiment of the present invention can be produced by this synthetic method or by a modified method of this synthetic method. Further, the salt of the compound according to the embodiment of the present invention can be obtained by performing an ion exchange treatment known per se according to the target salt after the synthesis by this method. These methods for synthesizing salts according to the present invention are also included in the scope of the present invention.

Compounds of general formula (I) according to the present invention and pharmaceutically acceptable salts thereof can be used to treat tumors such as malignant tumors. Malignant tumors include, for example, neurogenic tumors including brain tumors, and the following cancers classified into cancers such as squamous cell carcinoma and adenocarcinoma (head and neck cancer, skin cancer, esophageal cancer, thyroid cancer, gastric cancer, lung cancer, etc.) Biliary cyst cancer, biliary tract cancer, pancreatic cancer, liver cancer, prostate cancer, uterine cancer, ovarian cancer, breast cancer, renal cancer, bladder cancer, colon cancer, etc.), melanoma, bone / soft tumor, and lymphoma, leukemia, myeloma, etc. Is included, but is not limited to these. As used herein, "treatment" refers to shrinking, eliminating or suppressing the growth of a malignant tumor as described above, or any of the above.

In radiotherapy, for example, active oxygen species (ROS) are generated from oxygen, water molecules, etc. by irradiation with radiation, and cancer tissue is treated by gene damage and cell damage mediated by ROS. Here, the irradiation of radiation may be external irradiation using electron beams, X-rays, gamma rays, proton beams, heavy particle beams, or the like, or internal irradiation such as brachytherapy.

On the other hand, in the tumor microenvironment around the cancer tissue, cells often proliferate excessively, and angiogenesis cannot catch up with it, creating a hypoxic environment. In addition, since a large amount of antioxidant enzymes are present in the tumor microenvironment, it is difficult to generate ROS even when irradiated with radiation, and most of the produced ROS is also decomposed by the antioxidant enzymes, which is effective in treatment. Hard to get.

Here, for example, Non-Patent Document 2 indicates that 5-aminolevulinic acid (ALA) can be used as a radiosensitizer in photodynamic therapy. ALA is a substance that accumulates PpIX at a high concentration in tumor cells when taken up by a living body, and PpIX generates active oxygen by, for example, photoexcitation. Substances that generate active oxygen and cause gene damage in this way are used as radiosensitizers.

Compounds of general formula (I) according to the present invention and pharmaceutically acceptable salts thereof, when administered, accumulate in cancer tissues and induce the production of ROS. According to the examples described below, the compound of the general formula (I) and the pharmaceutically acceptable salt thereof have an amount of ROS equivalent to that of a known sulfoquinobosylacylpropanediol derivative used as a radiosensitizer. Induces the production of.

Therefore, the compound of general formula (I) according to the present invention and a pharmaceutically acceptable salt thereof can be used as an agent for releasing ROS in vivo. In addition, the compound of general formula (I) according to the present invention and its pharmaceutically acceptable salt shall be used as a pharmaceutical compound that enhances its effect in combination with radiation in tumor treatment by inducing its production of ROS. Can be done.

According to aspects of the present invention, the compound of general formula (I) and its pharmaceutically acceptable salt have a radiosensitizing effect. Therefore, the compounds of general formula (I) and pharmaceutically acceptable salts thereof may be provided as radiosensitizers.

The radiosensitizer according to the present invention is a group consisting of the compound of the general formula (I) described above, a pharmaceutically acceptable salt thereof, and a pharmaceutical derivative and a pharmaceutically acceptable salt thereof utilizing its pharmacological action. An effective amount of one or more selected from the above may be contained as an active ingredient. Further, the compound of the general formula (I) may be any of other radiosensitizers, antitumor agents or other substances having pharmacological activity or substances having pharmaceutical activity, as long as the activity is not adversely affected. It may be used in combination with or in combination with both.

In this case, the administration conditions of the compound of the general formula (I) (for example, dose, number of administrations, administration interval, etc.) are the administration form, administration route, target disease, for example, malignant tumor state (for example, for example). Types, location, stage of progression, etc.), conditions such as concomitant medications (eg, presence / absence of concomitant medications, type, amount, number of concomitant medications, timing of concomitant use and order of administration of the antineoplastic agent, etc.), and treatment It can be appropriately set and adjusted according to the condition of the subject to be received (for example, weight, gender, age, etc.).

The compound of the general formula (I) according to the present invention and a pharmaceutically acceptable salt thereof can be administered orally or parenterally, for example. Compounds of general formula (I) according to the present invention and pharmaceutically acceptable salts thereof are combined with appropriate pharmaceutically acceptable excipients or pharmaceutical additives such as diluents, depending on their routes of administration. Thereby, it can be made into a pharmaceutical preparation.

Dosage forms suitable for oral administration include solid, semi-solid, liquid or gaseous, specifically tablets, capsules, powders, granules, solutions, suspensions, etc. Examples thereof include, but are not limited to, syrup agents, elixir agents, aerosol agents, and the like.

When the compound of the general formula (I) according to the present invention and a pharmaceutically acceptable salt thereof are orally administered, they may be administered, for example, by injection, transdermal administration, rectal administration, intraocular administration and the like.

As the administration by injection, it can be administered subcutaneously, intradermally, intravenously, intramuscularly or the like.

The administration conditions (for example, dose, number of administrations, administration interval, etc.) of the compound of the general formula (I) according to the present invention and the pharmaceutically acceptable salt thereof are described in terms of administration form, administration route, target disease, for example. Conditions such as malignant tumor status (eg, type, location, stage of progression, etc.), concomitant medications (eg, presence / absence of concomitant medications, type, amount, number of concomitant medications, timing of concomitant use and order of administration of the compounds of the present invention) Depending on the method of concomitant use with radiation (for example, the timing of concomitant use and the order in which the radiation sensitizer of the present invention is administered), and the condition of the subject to be treated (for example, weight, gender, age, etc.). Can be set and adjusted as appropriate.

As an example, the compound of the general formula (I) according to the present invention and a pharmaceutically acceptable salt thereof are 0.001 to 100 mg / kg body weight / day when orally administered, and 0.001 to 100 mg / kg body weight / day when administered as an injection. 0.001 to 50 mg / kg body weight / day, 0.001 to 100 mg / kg body weight / day for transdermal administration, 0.001 to 50 mg / kg body weight / day for rectal administration, intraocular administration In the case of, the solution of about 0.001 to 3% can be set to be instilled several times a day, but the present invention is not limited to these.

On the other hand, in radiotherapy, the type, amount, and number of irradiations of radiation can be set to the same conditions as those of conventional radiotherapy. Specific examples of conventional human irradiation include medical radiation, such as X-rays, γ-rays, electron beams, β-rays, π-intermediate particles, neutrons, and other heavy particles. Examples thereof include those in which the line is irradiated for a period of 1 week to 6 months so that the total irradiation amount is about 10 to 500 Gy at an irradiation amount of about 0.1 to 100 Gy each time. Typical examples of human irradiation include, but are not limited to, X-rays that are irradiated with 2 Gy 5 times a week and a total of 60 Gy over about 6 weeks. .. For example, the irradiation amount and the number of irradiations can be reduced. In addition, the irradiation method can also be performed by active ingredient irradiation, stereotactic irradiation that pinpoints the lesion of a malignant tumor, intensity-modulated irradiation, or the like. In addition, irradiation with a sealed brachytherapy source, remote γ-ray irradiation, or irradiation with a particle beam can also be performed. In addition, it is possible to increase the irradiation amount and shorten the irradiation period by internal irradiation.

Irradiation and administration of the compound of general formula (I) according to the present invention and a pharmaceutically acceptable salt thereof may be carried out at the same time, but one of them may precede the other. In this case, the compound of the general formula (I) according to the present invention and a pharmaceutically acceptable salt thereof are expected to act as an antineoplastic agent used in combination with irradiation. Therefore, the compound of the general formula (I) according to the present invention and a pharmaceutically acceptable salt thereof may be provided as a pharmaceutical compound such as an antineoplastic agent used in combination with irradiation.

As is well known in the field of radiotherapy, the irradiation conditions of the above-mentioned radiation and the administration conditions of the compound of the general formula (I) according to the present invention and the pharmaceutically acceptable salt thereof are the type of radiation source, the irradiation method, and the irradiation site. And irradiation period; type of sensitizer, administration route and timing; type of disease to be treated and severity of disease; medical engagement depending on the age, weight, health condition, medical history, etc. of the subject to be irradiated. Can be appropriately selected by the person or other specialists.

Further, according to a further aspect of the present invention, it comprises administering an effective amount of the compound of the general formula (I) according to the present invention and a pharmaceutically acceptable salt thereof to a subject in need thereof. Treatment methods for diseases for which irradiation is beneficial are also provided. Here, the “disease for which irradiation is beneficial” refers to a disease such as the above-mentioned malignant tumor in which irradiation is beneficial for its treatment. Details of the compound of the general formula (I) according to the present invention and the pharmaceutically acceptable salt thereof, as well as the administration method and administration conditions may be as described above.

In addition, the therapeutic method according to the present invention provides an effective amount of the compound of the general formula (I) according to the present invention and a pharmaceutically acceptable salt thereof to a subject in need thereof at the same time as or by irradiation. It may be provided to be administered before and after irradiation.

In addition, as shown in Non-Patent Document 3, hydrolases such as lipase, protease, or glycosidase are generally increased in cancer cells. The compound of general formula (I) according to the present invention and its pharmaceutically acceptable salt do not have an ester bond and are therefore stable to, for example, lipase. In Example 2, which will be described later, the compound of general formula (I) according to the present invention and a pharmaceutically acceptable salt thereof are persistent in cancer tissue for a longer period of time as compared with a sulfopyranosyl acylpropanediol derivative. It has been shown to be effective as a sensitizer.

[Example 1]
Hereinafter, an example of a method for synthesizing the sodium salt represented by the structural formula (11) will be described as an example of the general formula (1). In this example, 3- (n-octadecyloxy) -n-propyl-α-D-quinovopyranoside sodium salt (in structural formula (11), Cm: n is an octadecyl group) is the path A described above. It was synthesized according to ~ J.

In route A, allyl-α-D-glucopyranoside (structural formula (2)) was synthesized. The 500 mL eggplant flask was replaced with argon, and allyl alcohol (250 mL) was added. To this, α-D-glucopyranose (structural formula (1)) (50 g) was added with stirring, and camphor-sulfonic acid (1.9 g) was added while cooling to 0 ° C. under ice water. Then, it was taken out from the ice bath, returned to room temperature, heated to 80 ° C., and stirred for 16 hours. Then, the compound of structural formula (2) was obtained as a residue concentrated under reduced pressure.

In route B, allyl-4,6-O-benzylidene-α-D-glucopyranoside (structural formula (2)) was synthesized. To the residue of Route A, add 100 mL each of anhydrous N, N-dimethylformamide and acetonitrile, cool to 0 ° C. under ice water, and cool to 0 ° C., benzaldehyde dimethylacetal (103 mL) and toluenesulfonic acid monohydrate (2.5 g). ) And was added. Then, after heating and stirring at 40 ° C. for 16 hours, triethylamine (10 mL) was added to stop the reaction and concentrate under reduced pressure. The residue was poured into hexane (180 mL) and water (150 mL) and the mixture was vigorously stirred. The resulting precipitate was filtered off and washed with cold water and hexane in that order. The precipitate is further washed with hexane, cold water, and hexane in this order and filtered, and the precipitate is crystallized from ethanol to form colorless acicular crystals of the compound represented by the structural formula (3) (28.6 g, 57. 2%) was obtained.

Mass spectrometry of the compound of structural formula (3) and ^{1 1} H-NMR spectrum are shown in FIGS. 1 and 2.

In this example, a mass spectrometer (manufactured by Shimadzu Corporation, AXIMA MALDI-7090 TOFMS) was used for mass spectrometry. Further, ^{the measurement of the 1} H-NMR spectrum below was carried out using a spectrometer (manufactured by JEOL, ECS400 400 MHz) using CDCl3 as a solvent. The data of the mass spectrometry of the compound of the structural formula (3) and the ¹ H-NMR spectrum are shown below.
MS: Measured value m / z 331.02 [M + Na] Calculated value 308.33 [M]
δ: 7.6-7.2 (5H), 6.0-3.5 (13H)

In route C, allyl-2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranoside (structural formula (4)) was synthesized. The compound (10.0 mg) of structural formula (3) was cooled to 0 ° C. under ice water, anhydrous N, N-dimethylformamide (181.5 mL) and 60% NaH (3.1 g) were added, and 10 at room temperature. Stirred for minutes. The mixture was cooled to 0 ° C. under ice water again, benzyl bromide (9.7 mg) was added, and the mixture was stirred at room temperature for 1 hour. Then, after neutralization by adding triethylamine (11.4 mL) and methanol (11.4 mL), the reaction solution was poured into cold water (900 mL) and extracted with ethyl acetate (300 mL, 3 times). After washing with saturated brine, the organic phase was dried over magnesium sulfate and filtered, and concentrated under reduced pressure to give a reaction product (17.92 g). This reaction product was produced by silica gel chromatography (mixed solution of hexane and ethyl acetate) to obtain a compound of structural formula (4) (4.9 g, 48.7%).

Mass spectrometry of the compound of structural formula (4) and ^{1 1} H-NMR spectrum are shown in FIGS. 3 and 4.

The data of the mass spectrometry of the compound of the structural formula (4) and the ¹ H-NMR spectrum are shown below.
MS: Measured value m / z 513.03 [M + Na] Calculated value 488.58 [M]
δ: 7.6-7.2 (15H), 6.0-3.5 (17H)

In route D, 3-hydroxy-n-propyl-2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranoside (structural formula (5)) was synthesized. Tetrahydrofuran of 0.5M 9-borabicyclo [3,3,1] nonane (9-BBN) in anhydrous tetrahydrofuran solution (150 mL) of compound (4) of structural formula (4) at 0 ° C. under an argon atmosphere. The solution (8.2 mL) was added. After 1 hour, the reaction solution was returned to room temperature, followed by stirring for 2 hours. Then, the reaction solution was cooled to 0 ° C. again, 3M sodium hydroxide solution (10 mL) and 30% hydrogen peroxide solution (1 mL) were sequentially added, and after 1 hour, the temperature was returned to room temperature and the mixture was stirred for 16 hours. After confirming that the reaction has proceeded sufficiently, this solution is extracted with ethyl acetate (100 mL, 3 times), the organic phases are combined, washed with saturated brine (100 mL, 2 times), and then with sodium sulfate. After drying and filtration, the mixture was concentrated under reduced pressure. The obtained residue (1.8 g) is dissolved in chloroform and purified by silica gel column chromatography (mixed solution of hexane and ethyl acetate) to obtain a colorless oil of the compound of structural formula (5) (1.0 g, 99.0). %) Was obtained.

Mass spectrometry of the compound of structural formula (5) and ^{1 1} H-NMR spectrum are shown in FIGS. 5 and 6.

The data of the mass spectrometry of the compound of the structural formula (5) and the ¹ H-NMR spectrum are shown below.
MS: Measured value m / z 529.28 [M + Na] Calculated value 506.68 [M]
δ: 7.6-7.2 (15H), 6.0-3.5 (16H), 2.0-1.8 (2H)

In route E, 3- (n-octadecyloxy) -n-propyl-2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranoside (structural formula (6)) is synthesized. It was. The compound (1.0 g) of the structural formula (5) is dissolved in N, N-dimethylformamide (10 mL), 60% NaH (0.3 g) is added while stirring at 0 ° C., and then the mixture is stirred at room temperature for 15 minutes. did. Then, stearyl bromide (1.3 g) was added, and the mixture was stirred at room temperature for 6 hours. 60% NaH (0.3 g) was added again, and the mixture was stirred at 40 ° C. for 1 hour. Then, the temperature was returned to room temperature, methanol (5 mL) was added to stop the reaction, and the mixture was concentrated under reduced pressure. The residue suspended in a small amount of ethyl acetate was poured into water (20 mL) and extracted with dichloromethane (10 mL, 3 times). The residue was extracted, the organic phase was washed with Milli-Q water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (mixed solution of toluene and ethyl acetate) to obtain a compound of structural formula (6) (1.0 g, 99.0%) as a colorless oily substance.

Mass spectrometry of the compound of structural formula (6) and ^{1 1} H-NMR spectrum are shown in FIGS. 7 and 8.

The data of the mass spectrometry of the compound of the structural formula (6) and the ¹ H-NMR spectrum are shown below.
MS: Measured value m / z 781.86 [M + Na] Calculated value 759.08 [M]
δ: 7.6-7.3 (15H), 5.7-3.3 (16H), 2.0-9.8 (39H)

In route F, 3- (n-octadecyloxy) -n-propyl-2,3,4-tri-O-benzyl-α-D-glucopyranoside (structural formula (7)) was synthesized. The compound (0.5 g) of the structural formula (6) was dissolved in dichloromethane (6.6 mL), and a tetrahydrofuran-borane-tetrahydrofuran solution and trimethylsilyl triflate (17.9 μL) were added under ice-cooling. The mixture was stirred at room temperature for 3 hours, and after confirming the progress of the reaction, triethylamine was added for neutralization. Water (10 mL) was then added and extracted with chloroform (100 mL, twice). The organic phase was washed with 1M HCl solution, sodium bicarbonate solution, and saturated brine in this order. Then, it was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (mixed solution of toluene and ethyl acetate) to obtain a compound of structural formula (7) (0.43 g, 85.3%).

Mass spectrometry of the compound of structural formula (7) and ^{1 1} H-NMR spectrum are shown in FIGS. 9 and 10.

The data of the mass spectrometry of the compound of the structural formula (7) and the ¹ H-NMR spectrum are shown below.
MS: Measured value m / z 784.69 [M + Na] Calculated value 761.10 [M]
δ: 7.6-7.3 (15H), 5.1-4.6 (17H), 2.0-9.8 (39H)

In pathway G, 3- (n-octadecyloxy) -n-propyl-2,3,4-tri-O-benzyl-6-O-tosyl-α-D-glucopyranoside (structural formula (8)) was synthesized. .. Paratoluenesulfonyl chloride (0.07 g) was added to a pyridine solution (0.50 mL) of the compound (0.10 g) of the structural formula (7) at 0 ° C. under ice water under an argon atmosphere, and the mixture was returned to room temperature and stirred for 4 hours. did. After confirming the completion of the reaction by thin film chromatography (TLC), the mixture was cooled to 0 ° C. under ice water and neutralized by adding methanol. Then, the residue suspended in a small amount of ethyl acetate was poured into 1M hydrochloric acid (1 mL) and extracted with ethyl acetate (2 mL, 3 times). Combine the organic phases, wash in the order of saturated saline (1 mL, 2 times), saturated sodium hydrogen carbonate water (1 mL, 2 times), saturated saline (1 mL, 2 times), dry with sodium sulfate, filter, and then. Concentrated under reduced pressure. The concentrate (0.146 g) was dissolved in chloroform and purified by silica gel chromatography (mixed solution of toluene and ethyl acetate) to obtain a compound of structural formula (8) (0.08 g, 95.3%).

Mass spectrometry of the compound of structural formula (8) and ^{1 1} H-NMR spectrum are shown in FIGS. 11 and 12.

The data of the mass spectrometry of the compound of the structural formula (8) and the ¹ H-NMR spectrum are shown below.
MS: Measured value m / z 938.61 [M + Na] Calculated value 915.28 [M]
δ: 7.8-7.2 (19H), 5.1-3.3 (11H), 2.5-0.8 (42H)

In pathway H, 3- (n-octadecyloxy) -n-propyl-2,3,4-tri-O-benzyl-6-thioacetyl-α-D-glucopyranoside (structural formula (9)) was synthesized. Absolute ethanol (1 mL) and potassium thioacetate (0.02 g) were added to the compound (0.05 g) of the structural formula (8) under an argon atmosphere, and the mixture was stirred at 80 ° C. for 4 hours. After confirming the progress of the reaction, cold water (1 mL) was poured under ice-cooling, and the mixture was extracted with ethyl acetate (3 mL, twice). Then, the organic phases were combined and washed with 1 M aqueous sodium hydroxide solution (1 mL, 2 times) and saturated brine (1 mL, 2 times) in this order, and the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (mixed solution of hexane and ethyl acetate) to obtain a compound of structural formula (9) (0.43 g, 85.3%) as a light brown oily substance.

Mass spectrometry of the compound of structural formula (9) and ^{1 1} H-NMR spectrum are shown in FIGS. 13 and 14.

The data of the mass spectrometry of the compound of the structural formula (9) and the ¹ H-NMR spectrum are shown below.
MS: Measured value m / z 841.49 [M + Na] Calculated value 819.20 [M]
δ: 7.4-7.2 (15H), 5.0-3.1 (17H), 2.5-0.8 (42H)

In route I, 3- (n-octadecyloxy) -n-propyl-2,3,4-tri-O-benzyl-α-D-quinovopyranoside sodium salt (structural formula (10)) is synthesized. It was. Glacial acetic acid (3.4 mL), potassium acetate (0.35 g), and OXONE (0.13 g) were added to the compound (0.05 g) of the structural formula (9) in this order, and the mixture was vigorously stirred at room temperature for 4 hours. After confirming that the reaction had proceeded sufficiently, the reaction solution was poured into cold water (5.4 mL) and stirred. Then, the mixture was extracted with ethyl acetate (2 m, 2 times), the organic phases were combined, washed with saturated aqueous sodium hydrogen carbonate solution (2 mL, 2 times) and saturated brine (2 mL, 2 times) in this order, and dried over sodium sulfate. After filtration, the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (mixed solution of dichloromethane and methanol) to obtain a compound of structural formula (10) (0.01 g, 37.6%) as a colorless wax-like substance.

Mass spectrometry of the compound of structural formula (10) and ^{1 1} H-NMR spectrum are shown in FIGS. 15 and 16.

The data of the mass spectrometry of the compound of the structural formula (10) and the ¹ H-NMR spectrum are shown below.
MS: Measured value m / z 824.43 [M-Na] Calculated value 847.14 [M]
δ: 7.4-7.2 (15H), 5.0-3.1 (17H), 2.5-0.8 (39H)

In route J, a 3- (n-octadecyloxy) -n-propyl-α-D-quinovopyranoside sodium salt (structural formula (11)) was synthesized. The compound (0.007 g) of the structural formula (10) was dissolved in ethanol (1.6 mL), palladium carbon (0.032 g) was added, and the mixture was stirred at 30 ° C. for 16 hours under a hydrogen gas atmosphere. After confirming that the reaction had proceeded sufficiently, the palladium activated carbon was filtered off and the filtrate was concentrated under reduced pressure. Methanol (2 mL) and toluene (2 mL) were added to the obtained residue, and the mixture was vigorously stirred, and then the solvent was evaporated under reduced pressure to obtain a colorless liquid mixture. The concentrated residue was purified by silica gel column chromatography (mixed solution of chloroform and methanol) to obtain a compound of structural formula (11) (0.004 g, 81.6%).

Mass spectrometry of the compound of structural formula (11) and ^{1 1} H-NMR spectrum are shown in FIGS. 17 and 18.

The data of the mass spectrometry of the compound of the structural formula (11) and the ¹ H-NMR spectrum are shown below.
MS: Measured value m / z 556.16 [M + Na] Calculated value 576.33 [M]
δ: 5.0-2.8 (17H), 4.8-2.8 (11H), 1.0-0.8 (37H)

[Test as a candidate compound for radioactive sensitizer]
Hereinafter, as the test compound, the compound of the structural formula (11) (compound (A)) and the sulfopyranosylacylpropanediol derivative (compound (B)) described in Patent Document 2 used as a radiosensitizer. And are used, respectively, and the results are shown in FIGS. 20 and 21 for each test.

Fetal bovine serum (FBS) (manufactured by Sigma-Aldrich) was added to RPMI1640 (manufactured by Sigma-Aldrich) to a final concentration of 10%. Further, penicillin G potassium (manufactured by Meiji Seika) and streptomycin (manufactured by Meiji Seika) were added so as to be 0.1 mg / mL, respectively, and used as a culture solution in the following. Hereinafter, as a reagent, a CellROX Green Reagent solution (manufactured by Thermo Fisher Scientific Co., Ltd.) was used.

Human alveolar basal epithelial adenocarcinoma cell line A549 cells were suspended in RPMI1640 medium (1.0 × 10 ^ 5 cells / mL), and 100 μL was dispensed into 96-well-plate. Then, the cells were cultured under 37 ° C. and 5% CO ₂ saturation conditions to be attached to a plate, and after culturing for 24 hours, the medium was removed by suction, and the cells were washed with PBS. Then, PBS and the test compound suspended in PBS (containing 10% PBS) were added separately by 100 μL. After culturing the medium under 37 ° C. and 5% CO ₂ saturation conditions for 1 hour, CellROX Green Reagnanto solution was added to each well to a final concentration of 5 μL, and then again at 37 ° C. and 5% CO ₂ saturation. The cells were cultured for 30 minutes under the conditions. After the completion of the culture for 30 minutes, the cells were washed with PBS, and the fluorescence intensity at an excitation wavelength of 485 nm and a detection wavelength of 520 nm was confirmed. The ROS production amount ratio of each test compound was calculated with the value of the fluorescence intensity of well to which only PBS containing no test compound was added as 1.

The ROS production amount ratio calculated here is shown in FIG. Compound (A) was found to induce ROS production in human alveolar basal epithelial adenocarcinoma cell line A549 cells, similar to sulfopyranosyl acylpropanediol derivatives such as compound (B). Therefore, the compound of the general formula (I) according to the present invention and a pharmaceutically acceptable salt thereof can be used as a radiosensitizer or a reagent for releasing active oxygen in vivo.

[Test of hydrolysis resistance]
The test compound and lipase for organic synthesis (Fujifilm Wako Pure Chemical Industries, Ltd., Lipase PS Amano SD) were adjusted with PBS so as to be 1.3 μg / μL, respectively. Then, the reaction solution was developed by TLC using a developing solvent (chloroform: methanol = 1: 1) and analyzed. As the reaction solution to be developed, samples at 2 hours and 4 hours before the reaction proceeded were used. In addition, for the reaction solution using compound (A) as the test compound, the sample at 18 hours after the reaction was also analyzed. As TLC, TLC aluminum sheet silica gel 60 F254 (manufactured by Merck) was used.

The result of the analysis is shown in FIG. When a sulfopyranosyl acylpropanediol derivative such as compound (B) was used as the test compound, it was confirmed that the test compound was completely decomposed 4 hours after the start of the reaction. On the other hand, when compound (A) was used as the test compound, it was confirmed that the test compound was not completely decomposed even at 18 hours after the reaction. From this result, it was shown that the compound (A) has better hydrolysis resistance than the sulfopyranosyl acylpropanediol derivative.

Therefore, the compound of general formula (I) according to the present invention and its pharmaceutically acceptable salt are stable to lipase and last longer in cancer tissues as compared to sulfopyranosyl acylpropanediol derivatives. It has been shown to be effective as a persistent sensitizer.

The invention is not limited to the above-described embodiment, and various modifications and changes can be made within the scope of the gist of the invention.

Claims (2)

A compound represented by the following formula (I) or a salt thereof.

In the formula (I), R ₁ is an aliphatic hydrocarbon group of C _{10 to} C _26. The compound according to claim 1 , or a salt thereof, wherein R ₁ is an octadecyl group.

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